Review of Adverse Effect Profile, Safety, and Dosing of Antidepressants

n 2002, 8.5% of the US population purchased at least one prescription antidepressant.1 Given this relatively high rate of antidepressant use, best practices should be followed in choosing the correct medication and dosing, to avoid adverse events or ineffective treatment. Two of the major classes of antidepressants that are more commonly prescribed are the selective serotonin reuptake inhibitors (SSRIs) and the tricyclic antidepressants (TCAs). The SSRIs are generally the antidepressants of first choice. They are relatively safe and effective. The Cochrane Collaboration reviewed 32 well-conducted trials and found SSRIs to be just as effective as TCAs with fewer adverse effects in the elderly population.2 In the inpatient population, TCAs appear to be slightly more effective than SSRIs, but TCAs were noted to have decreased tolerability.3 Given the popularity and tolerability of SSRIs, this review focuses mainly on this group of antidepressants and also touches on some of the newer unique antidepressants.

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Doctors commonly enlist the power of placebos

Doctors prescribe placebos more often than patients might imagine.

A survey of Chicago-area physicians found that 45 per cent report they have given a patient a placebo at least once, according to a study published in this month's Journal of General Internal Medicine.

Past surveys of Israeli and Danish doctors revealed that 60 per cent and 85 per cent, respectively, admit they've relied on the "placebo effect" to heal patients.

So, should patients worry about their doctors shamming them?

Maybe not. Though prescribing dummy pills is viewed as ethically shady, the placebo effect can work. Brain-scan research indicates that placebos trigger pain-relieving endorphins in the brain. Indeed, anyone who has ever felt better after taking cough syrup may have enjoyed the placebo effect - some studies suggest that sugar water is just as good at healing sore throats. Belief in medicine can contribute heavily to its success.

Doctors turn to placebos for a variety of reasons, according to the Chicago study, including to calm the patient, as a last resort when nothing else works, or simply to get a patient to stop complaining.

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The Politics Of Depression

There was a fascinating exchange of letters in this month's American Journal of Psychiatry concerning just how much depression doctors should accept in their patients and the implications of such decisions. What prompted the initial letter was the federally-funded STAR-D trial, which showed that current depression treatments--including some psychotherapies--are no where near as robust as doctors (and presumably patients) would like. What the trial showed, in short, was that various anti-depressants had anywhere from an 8 percent to 30 percent chance of success in remitting symptoms of depression.

That leaves a large subset of people who do not get relief using current therapies and that raises a host of practical issues for the mental health field. This situation affects millions of Americans.

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Metformin and Counseling Retard Drug-Induced Weight Gain in Schizophrenia

For patients with schizophrenia taking antipsychotics, metformin or lifestyle counseling, or both combined, helps steer clear of drug-induced weight gain and insulin resistance, found investigators here.

In a randomized 12-week trial of 128 adults with schizophrenia, age 18 to 49, who had gained more than 10% of their pre-antipsychotic weight, metformin alone was more effective than lifestyle intervention alone, found Jing-Ping Zhao, M.D., Ph.D., and colleagues at the Second Xiangya Hospital here.

But a combined approach produced the better results, the research team reported in the Jan. 9/16 issue of the Journal of the American Medical Association.

Participants taking antipsychotic medications were randomized to one of four groups: 12 weeks of placebo, 750 mg/day of metformin alone, 750 mg/day of metformin with lifestyle intervention, or lifestyle intervention alone.

The lifestyle interventions included counseling and dietary and exercise programs, the researchers reported. Caregivers reported participants' food intake and exercise levels, the authors said.

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Effect of antidepressant warnings moderate-US study

Warnings that antidepressants might increase the risk of suicidal behavior in youth curbed rapid growth of these drugs but did not eliminate access to them among young people as some had feared, U.S. researchers said on Monday.

They said that while antidepressants had been growing at an annualized rate of 36 percent before regulators made the warnings in 2003, that growth flattened out after the warnings were issued.

Doctors have assumed that a spike in teen suicide in 2004 reulted from a sharp fall in use of antidepressants among children and youth.

That was not the case, according to Dr. Mark Olfson of Columbia University Medical Center.

"When the warnings first appeared, there was a great deal of concern among psychiatrists and other mental health professionals that these warnings would result in a precipitous decline in antidepressant use by young people, and as a result, youth with depression would have less access to treatment," said Olfson, whose study appears in the Archives of General Psychiatry.

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New treatment mechanisms for schizophrenia

The field of schizophrenia research has come alive with many exciting new potential approaches to treatment. From the introduction of chlorpromazine to the current day, all treatments approved by the U.S. Food and Drug Administration have had, at their core, a single treatment mechanism, the blockade of the dopamine D2 receptor. The introduction of clozapine in the 1980’s suggested a potential that other brain targets might complement the blockade of dopamine D2 receptors to treat symptoms that failed to respond to the “typical” antipsychotics. We are now entering an age where new treatments are being rationally developed within the context of translational neuroscience, i.e., the steps whereby basic molecular neuroscience leads to fundamental new mechanisms that can be tested in animal and human laboratory-based research that, in turn, leads to tests of new medications in our clinics. The January 1st issue of Biological Psychiatry includes encouraging new research related to three new treatment approaches.

In the first study, Olszewski and colleagues tested a novel drug that inhibits the breakdown of the transmitter N-acetylaspartylglutamate (NAAG), which activates a receptor that reduces schizophrenia-like behaviors in some animal models. Their findings indicate that this drug is effective in an animal model of schizophrenia. Joseph H. Neale, Ph.D., lead author on this project, comments, “While treating patients with receptor agonists can be highly effective therapy, drugs that increase the action of the transmitter that activates the same receptor have traditionally been very effective with fewer side effects than chronic agonist treatment.” He adds, “These data support the conclusion that NAAG peptidase inhibitors represent a breakthrough in the discovery of a completely novel means of adjunct therapy for schizophrenia that is analogous to the use of SSRIs [selective serotonin reuptake inhibitors] for the treatment of depression."

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Genetic variant predicts antipsychotic response for schizophrenia patients by ethnicity

Schizophrenia is a developmental disorder with a large genetic component contributing to increased risk. Available antipsychotic medications treat some of the symptoms of schizophrenia, but are typically effective in only a subset of patients. Unfortunately, it is difficult to predict the effectiveness of a specific drug in any given individual with schizophrenia. John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, notes that “in this era of medicine, the selection of particular antipsychotic medications for particular patients with schizophrenia is more art than science. We have been seeking objective guides, perhaps biological tests, which would inform this process.” A new study published in the January 1st issue of Biological Psychiatry provides some interesting data to aid in that goal.

The authors report that differential effectiveness of antipsychotic treatment was predicted, in a subset of patients with schizophrenia, by variants of the gene encoding for the regulator of G-protein signaling 4 (RGS4), a protein that regulates the functional consequences of activating neurotransmitter receptors. Dr. Daniel Campbell, corresponding author for this article, explains these results: “By applying genetic analysis to the NIMH-funded Clinical Antipsychotic Trials of Intervention Effectiveness, we show that variants in a specific gene, RGS4, predict the effectiveness of different antipsychotic treatments. Our results also indicate that the predictive power of the RGS4 genetic variants differed between patients of self-reported African and European ancestry, and thus emphasize the importance of including multiple ethnic groups in a study.”

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Antidepressants Help HIV-Infected Patients Stick to Treatment

People with HIV who suffer from depression are much less likely to stick with their treatment regimens, new research shows.

However, treating their depression with widely used selective serotonin reuptake inhibitor (SSRI) antidepressants can get them back on track, the researchers said.

A team from Kaiser Permanente in Oakland, Calif., analyzed the mental health, disease progression and treatment data of almost 3,400 HIV-infected patients nationwide between 2000 and 2003. All patients were starting a new, highly active antiretroviral therapy (HAART).

Reporting in the current online issue of the Journal of Acquired Immune Deficiency Syndromes, they found that almost half of the study participants (42 percent) had depression during the 12-month study. Those who were depressed were less likely to take their medications and had worse viral response than people who were not depressed. However, when depressed people took prescribed SSRIs -- which include drugs such as Celexa, Paxil, Prozac and Zoloft -- they had the same health outcomes as patients who were not depressed.

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Alcoholics With Depression Less Likely To Stay Sober

It’s hard to stay on the wagon when you’re depressed, according to a new study of problem drinkers.

Researchers from the Minneapolis VA Medical Center documented the quitting success of 462 people who tried to simultaneously give up alcohol and cigarettes.

At the beginning of the study, participants smoked at least five cigarettes a day and were alcohol dependent. Among the group, typical problematic drinking symptoms included repeatedly imbibing more than planned, difficulty quitting or cutting down, and continuing to drink even though drinking caused problems such as hangovers or sleeping difficulty.

All participants received intensive alcohol and smoking cessation treatment. Up to a year and a half later, researchers surveyed the participants and asked about their alcohol and tobacco habits.

READ MORE @ SCIENCE DAILY

Antipsychotics No Better than Placebo for Aggression in the Intellectually Disabled

Antipsychotic drugs do not reduce aggression in patients with an IQ below 75, despite common but controversial use for that purpose in the community.

Although aggression decreased substantially whether patients were given a typical or an atypical antipsychotic, the greatest improvements were seen with placebo (65%, 58%, and 79% from baseline, P=0.06), reported Peter Tyrer, M.D., of Imperial College here, and colleagues in the Jan. 5 issue of The Lancet.

"Antipsychotic drugs should no longer be regarded as an acceptable routine treatment for aggressive challenging behavior in people with intellectual disability," they said, even in low doses.

However, the medications may still have a place in treatment of some behavior disturbances among people with intellectual disability, they said, such as for autistic behavior disturbance in children and to prevent further aggressive behavior after the drugs are given as an emergency measure.

READ MORE @ MEDPAGE TODAY

Tips To Prevent Adverse Drug Events In Older Adults

Adverse drug events are more common in older adults because they are prescribed more drugs and are effected differently by these drugs than their younger counterparts. A review article written by Tufts University School of Medicine clinicians, published in American Family Physician, summarizes steps that physicians and other healthcare providers can take to avoid overuse, misuse, and underuse of medication in older adults.

"About one in three older persons taking at least five medications will experience an adverse drug event each year, and about two-thirds of these patients will require medical attention. Approximately 95 percent of these reactions are predictable, and about 28 percent are preventable," cite the authors, Cung Pham, MD, fellow in the Tufts University Family Medicine Residency at Cambridge Health Alliance's Malden Family Medicine Center, and Robert Dickman, MD, Jaharis Family Chair of Family Medicine at Tufts University School of Medicine.

Pham and Dickman summarize interventions for reducing inappropriate prescriptions as follows, while noting that there is limited research to support clear interventions.

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Most Free Drug Samples Go to Wealthy and Insured

Study undercuts notion that they're given to help the poor, some experts say

Most free drug samples go to wealthy and insured patients, not to the poor and uninsured who may need them most, Harvard researchers report.

In fact, more than four-fifths of those who receive samples are insured, while less than one-fifth are uninsured and less than one-third have low incomes (below $37,000 for a family of four), the researchers found.

"Free drug samples influence prescribing and also introduce potential safety problems," said lead researcher Dr. Sarah Cutrona, a physician with the Cambridge Health Alliance and an instructor of medicine at the Harvard Medical School. "Despite these problems, many doctors support the program because [they say] free samples 'allow us to get free medications to our neediest patients,' " she said.

However, most free samples don't go to the neediest patients, Cutrona's group found.

READ MORE @ US NEWS & WORLD REPORT

Some Antipsychotic Drugs May Be Missing Their Mark

Drugs that treat depression, schizophrenia and other psychotic conditions and that target a particular protein on brain cells might not be triggering the most appropriate response in those cells, new research suggests.

The study by researchers at The Ohio State University Medical Center examined the serotonin 2A receptor, a protein on brain cells sensitive to the neurotransmitter serotonin.

This study examined the early chemical events that happen inside neurons when the 2A receptor is stimulated by serotonin and by a synthetic hallucinogenic agent that is thought to mimic serotonin.

The findings, published online in the early edition of the Proceedings of the National Academy of Sciences with an accompanying editorial, show that although both compounds combine with and activate this receptor, they trigger different chemical pathways inside the neuron.

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They Have Beds, but Not the Ones They Want

NORMAN BLOOMFIELD sat hunched over on his sagging twin bed at Surf Manor, a small adult home in Coney Island, and wondered why he was still there.

An elfin man with a shock of fine gray hair, Mr. Bloomfield, 60, spent three months in the psychiatric ward of Maimonides Medical Center in 2001. He then applied to Surf Manor, a faded red brick building on a bleak stretch of Surf Avenue, thinking it would serve as a temporary residence between the hospital and independent housing.

But his months at Surf Manor have turned into years, because he cannot find another place to live.

Surf Manor is one of 65 private, state-licensed facilities in the city that house a total of more than 8,000 residents. These institutions, known as adult homes, have become de facto repositories for people who have psychiatric disorders but who, like Mr. Bloomfield, can live independently.

“Some people need day-to-day assistance, but some are extremely high functioning,” Mr. Bloomfield said one afternoon in his drab yellow room, which he shares with a roommate. “It’s unfair and irrational when people who could be independent end up in a place like this and languish for years.”

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Lilly’s Zypreza, Pfizer’s Geodon could see reimbursement restrictions next year

Psychiatric drugs like Eli Lilly’s Zyprexa could be next on the list for reimbursement restrictions based on comparative effectiveness data, experts in the field told Pharmawire.

The move would also spell trouble for AstraZeneca’s Seroquel and Pfizer’s Geodon, two commonly prescribed and costly antipsychotics. Cost pressures will be felt most acutely starting in June, when the patent expires on Johnson & Johnson’s competing product Risperdal.

Public and private payers have been fueling the growing interest in compiling data that allows them to compare different drugs within the same therapeutic category. The information then helps shape reimbursement programs - like step therapy, where patients are required to try a cheaper drug before a more expensive one will be covered.

Tanisha Carino, a director at research firm Avalere Health and former policy analyst at the Centers for Medicare and Medicaid Services, noted that mental health is a prime target for using comparative effectiveness data to make coverage decisions.

The National Institute of Mental Health is already sponsoring the large-scale Clinical Antipsychotics Trials of Intervention Effectiveness (also known as CATIE), which have shown that older, less expensive drugs can be as effective as newer ones. The data is rife with cost effectiveness comparisons.

READ MORE @ FINANCIAL TIMES

FDA Safety Changes: Pexeva, Vfend, Suprane

The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risk for serotonin syndrome in patients receiving concomitant treatment with paroxetine mesylate and triptans, drug interactions between voriconazole and efavirenz requiring dose adjustments for both drugs when used concomitantly, and the risk for respiratory adverse events associated with use of desflurane in certain pediatric settings.
Concomitant Use of Paroxetine Mesylate (Pexeva) and Triptans Linked to Risk for Serotonin Syndrome On December 9, 2006, the FDA approved safety labeling revisions for paroxetine mesylate (Pexeva tablets, made by Synthon Pharmaceuticals, Ltd) to advise of the potential increased risk for serotonin syndrome in patients receiving concomitant treatment with other serotonergic drugs (including 5-hydroxytryptamine-receptor agonists [triptans]) or drugs that impair serotonin metabolism (including monoamine oxidase inhibitors [MAOIs]).

Concurrent treatment with paroxetine and MAOIs is therefore contraindicated. Concomitant use of other selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), or the serotonin precursor tryptophan is not recommended. Caution is advised when using paroxetine in combination with other drugs or agents that can affect serotonergic neurotransmitter systems, such as the antibiotic linezolid (a reversible nonselective MAOI), lithium, tramadol, St. John's Wort, and triptans.

According to the FDA, rare postmarketing cases of serotonin syndrome have been reported with use of SSRIs and triptans. Associated symptoms may include changes in mental status (eg, agitation, hallucinations, and coma), autonomic instability (eg, tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (eg, hyperreflexia and incoordination), and/or gastrointestinal tract symptoms, such as nausea, vomiting, and diarrhea.

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Dementia Drugs a Danger to Seniors - Warnings lost in reams of drug company literature

A group of drugs that can have serious adverse effects when used by the elderly continues to be widely prescribed in Canada and the United States, despite concerns about their safety.

The drugs, called atypical antipsychotics, are used to manage the behavior of seniors who have dementia, but many experts consider them to be dangerous and possibly ineffective in elderly patients.

In 2005, both Health Canada and the Food and Drug Administration (FDA) in the United States warned that atypical antipsychotic medications increased the risk of death among elderly patients with dementia.

The Health Canada warning stated that in 13 scientific studies, elderly patients with dementia who were prescribed atypical antipsychotics had a 60 percent higher death rate on average than similar patients taking placebos.

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Searching for Similar Diagnosis Through DNA

The girls had never met, but they looked like sisters.

There was no missing the similarities: the flat bridge of their noses, the thin lips, the fold near the corner of their eyes. And to the families of 14-year-old Samantha Napier and 4-year-old Taygen Lane there was something else, too. In the likeness was lurking an explanation for the learning difficulties, the digestion problems, the head-banging that had troubled each of them, for so long.

Several of the adults wiped tears from their eyes. “It’s like meeting family,” said Jessica Houk, Samantha’s older sister, who accompanied her and their mother to a Kentucky amusement park last July to greet Taygen.

But the two families are not related, and would never have met save for an unusual bond: a few months earlier, a newly available DNA test revealed that Samantha and Taygen share an identical nick in the short arm of their 16th chromosomes.

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An active ingredient in treating mild depression

Study supports findings that exercise can help beat the blues and might reduce need for medication.

This fall, we ran a series of articles called Healthwatch that examined the latest medical studies making the news. The series provoked a lot of discussion, and readers asked for more, so medical journalist Evra Taylor Levy and emergency physician Eddy Lang are back, helping to make sense of sometimes contradictory medical research. Healthwatch runs every other week as a regular Gazette feature. The writers invite you to join them in their online forum. See details on Page D3.

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It's no secret that the holidays and transition into a new year spell depression for many people experiencing loneliness, difficult life events or loss. With this, our end-of-the-year edition of Healthwatch, we bring you an uplifting study that looks at a way of beating some kinds of depression without medication.
Worldwide, depression is the leading cause of years lived with disability. During their lifetime, about five to 12 per cent of men and 10 to 25 per cent of women will have at least one major depressive episode. Interestingly, mood disorders often begin in adolescence, making early diagnosis especially important to offset years of unhappy, impaired living. Additionally, Canadian winters mean reduced sunlight and shorter days, which have been implicated in an increased prevalence of depression at this time of the year.

Symptoms of depression

It has been reported that half of the people who have clinical depression don't know it, so recognizing its symptoms is essential and the first step toward treatment. While not a complete list, symptoms include: persistent sadness; pessimism; feelings of guilt; loss of interest and pleasure in activities; helplessness or hopelessness; difficulty concentrating; insomnia or oversleeping; apathy; anxiety; thoughts of suicide or death.

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Illuminating a seasonal disorder

About this time each year, Lisa Morris starts yearning for more light in her life.

The 31-year-old mother of two from Middle River suffers from seasonal affective disorder (SAD), a condition that prompts her to turn on a specially designed fluorescent lamp for up to an hour every morning when she rises.

Purchased from a medical supply outlet, the light helps ward off the ailment's most common symptoms: persistent fatigue, oversleeping and an increased appetite for sugary and starchy foods that often leads to weight gain.

"The light therapy does do the trick - but I still have my moments where I just want to go up and lay down in my room and not get up," Morris says.

The winter solstice occurred shortly after 1 a.m. today - the lowest point in a pattern of diminishing sunlight that begins each fall as the tilt of the earth's axis sends the northern hemisphere away from the sun. Today we get only 9 hours of sun.

Although SAD symptoms typically begin in September and October as the days get shorter, experts say the solstice period is when the effects of seasonal depression can be most pronounced, particularly if the condition is left untreated.

"It can really affect people for a major chunk of their lives, in a big way," said Dr. David Neubauer, a Johns Hopkins psychiatrist.

READ MORE @ BALTIMORE SUN